Enhancing engineered T cell therapeutic efficacy for the treatment of pancreatic ductal adenocarcinoma

项目摘要 胰腺导管腺癌（PDA）是一种高致死性恶性肿瘤，5年总生存率<10%。 致死性是由于诊断晚，早期转移和治疗耐药。PDA的一个标志性特征是 是强大的纤维炎性和抑制性肿瘤微环境，其压缩血管， 限制了毒品的获取。这种肿瘤微环境也被认为会干扰免疫治疗， 改变了许多其他癌症适应症的护理标准。肿瘤抗原特异性T细胞是 负责介导免疫疗法的治疗效果。虽然我们已经了解了很多 胰腺肿瘤微环境中的抑制细胞，影响分化程序的因素 抗原特异性T细胞及其抗肿瘤活性在这种疾病中的研究明显不足。我们创建了一个 一种新的工程化T细胞疗法，其在侵袭性和非侵袭性肿瘤中显示出显著的抗肿瘤和抗基质活性， 难以治疗的遗传工程PDA动物模型概括了人类疾病的许多方面， 包括对免疫疗法的反应。T细胞被工程化以表达特异于肿瘤的肿瘤反应性T细胞受体， 间皮素在肿瘤细胞中高度表达，而在正常细胞中表达很少，它是安全的，可以破坏肿瘤细胞， 间质，改变骨髓细胞组成，诱导客观反应，并显著降低动物存活率。 值得注意的是，工程化T细胞优先在原发性肿瘤和转移中积累，挑战了传统的理论。 PDA是免疫豁免的基于这种功效，可使用特异于间皮素的候选T细胞受体， 已经确定了导致1期临床试验的患者。然而，尽管工程化T细胞持续存在， 和显著的体内抗肿瘤活性，治疗的主要障碍是工程化T细胞的进行性损失 在抑制性胰腺肿瘤微环境中发挥作用。虽然T细胞的功能和分化 在其他癌症适应症中得到了充分研究，但关于胰腺肿瘤如何 微环境影响肿瘤抗原特异性T细胞。在这里，我们将我们拥有的创新工具 开发用于确定工程化T细胞如何介导基质重塑，肿瘤如何适应 并避开抗肿瘤T细胞，然后利用这些知识开发尖端的工程T细胞疗法， 与大多数细胞工程方法相比，对于患者治疗具有战略性进步。我们 具体目的是：（1）确定工程化T细胞如何介导基质重塑，（2）确定在细胞增殖和分化中的作用。 TCR亲和力和肿瘤微环境对T细胞分化和功能的影响，以及（3）测试安全性 和靶向实体瘤的新型细胞工程方法的功效。我们的研究将确定 T细胞和肿瘤微环境的特征，在肿瘤发生过程中产生持久的抗肿瘤反应。 免疫疗法为胰腺癌患者的治疗创造了安全和持久的临床机会。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with a 5-year overall survival of <10%. Lethality is due to late diagnosis, early metastasis and therapeutic resistance. A hallmark characteristic of PDA is the robust fibroinflammatory and suppressive tumor microenvironment that compresses blood vessels and restricts drug access. This tumor microenvironment is also believed to interfere with immunotherapies, which are transforming the standard of care for many other cancer indications. Tumor-antigen specific T cells are responsible for mediating the therapeutic effects of immunotherapy. While much has been learned about suppressive cells within the pancreatic tumor microenvironment, factors that impact the differentiation program of antigen-specific T cells and their antitumor activity is markedly understudied in this disease. We created a novel engineered T cell therapy that shows marked anti-tumor and anti-stromal activity in an aggressive and difficult to treat genetically engineered PDA animal model that recapitulates many aspects of the human disease, including response to immunotherapy. T cells engineered to express a tumor-reactive T cell receptor specific to mesothelin, which is highly expressed by tumor cells yet poorly expressed by normal cells, is safe, destroys the stroma, alters myeloid cell composition, induces objective responses, and significantly prolongs animal survival. Notably, engineered T cells preferentially accumulate in primary tumors and metastasis, challenging the dogma that PDA is immune privileged. Based on this efficacy, candidate T cell receptors specific to mesothelin for use in patients have been identified leading to a Phase 1 clinical trial. However, despite engineered T cell persistence and significant antitumor activity in vivo, a principle obstacle to cure is the progressive loss of engineered T cell function within the suppressive pancreatic tumor microenvironment. While T cell functionality and differentiation are well-studied in other cancer indications, little is understood regarding how the pancreatic tumor microenvironment impacts tumor antigen-specific T cells. Here, we incorporate innovative tools we have developed to identify mechanistically how engineered T cells mediate stromal remodeling, how the tumor adapts and evades anti-tumor T cells, and then use this knowledge to develop a cutting edge engineered T cell therapy for patient treatment with strategic advancements as compared to most cell engineering approaches. Our Specific Aims are to: (1) Identify how engineered T cells mediate stromal remodeling, (2) Identify the contribution of TCR affinity and the tumor microenvironment on T cell differentiation and functionality, and (3) Test the safety and efficacy of a novel cell engineering approach for targeting solid tumors. Our studies will identify characteristics of T cells and the tumor microenvironment that produce durable antitumor responses during immunotherapy to create safe and durable clinical opportunities for pancreatic cancer patient treatment.